The training goal for this ambitious proposal is to provide the fellow, in a stepwise fashion, with increasing levels of independence and responsibility in an interdisciplinary study of complex disease. The research goal of this proposal is to identify the genetic variants which confer susceptibility to type 2 diabetes mellitus (T2DM) in African Americans and gain insight into their mechanism of action. This goal will be attained through 1) Replication of significant findings identified from the genome wide association (GWA) analysis of >650,000 SNPs for association with T2DM, 2) Validation of T2DM associations and exploration of the physiological mechanism through which these variants modulate T2DM susceptibility in additional populations, 3) Fine mapping of the genomic regions consistently showing association with T2DM and identifying trait predisposing variants and ultimately 4) Utilize molecular biology techniques to determine the biological mechanism through which identified T2DM-susceptibility variants exert their effects in vivo. These experiments will provide confirmation of involvement in disease progression and determine the role of these loci in vivo. Taken together, this proposal integrates modern genomic approaches, clinical methodologies and biochemical assays to increase the likelihood of identifying genes which contribute to T2DM susceptibilty. With this approach, the fellow will be supported to develop independence through a comprehensive network of interactive researchers in the fields of epidemiology, statistics, biochemistry, physiology. This will provide the skills and experience to independently direct an interdisciplinary study of the genetics of common disease.